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Endocannabinoid Release Can Combat Seizures But Leads to Stroke-like Aftereffects, Study Finds

By Alexander Beadle

Published: Aug 11, 2021   
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Epileptic seizures trigger the rapid synthesis and release of the endocannabinoid 2-arachidonoylglycerol (2-AG) in the brain, new research published this month in Neuron has found.

The release of this compound helped to aid the body in suppressing the root of seizure activity in the brain’s hippocampus. However, the researchers also found that 2-AG is broken down rapidly in the body after its release, triggering new biochemical reactions that cause the blood vessels in the brain to constrict. This effect may explain the disorientation and amnesia often seen shortly after seizure has taken place.

The research team, led by senior researchers at Stanford University and the University of Calgary in Alberta, believe that their findings could help guide the development of new drugs that are able to dampen the strength of epileptic seizures and reduce their potential aftereffects.

Scientists used new technique to study endocannabinoids in real-time

Epileptic seizures are generally caused by a period of dramatically heightened electrical activity in the brain. This hyperactivity can affect crucial areas of the brain, commonly resulting in a loss of consciousness and convulsions.

For the majority of adults, seizures tend begin in the hippocampus, a part of the brain that plays a significant role in managing short-term memory, learning, and spatial orientation. But in order to fulfil these tasks, the hippocampus must be able to ​​quickly adopt new neuronal firing patterns. This adaptability makes the hippocampus especially vulnerable to the misfiring patterns that cause seizures.

Endocannabinoids are a class of signaling compounds produced by the body that target part of the nervous network called the endocannabinoid system. This is the same system targeted by the psychoactive components in the cannabis plant; both cannabinoids and endocannabinoids share an affinity for a receptor known as cannabinoid receptor 1 (CB1).

Prior to this study, it was already known that certain endocannabinoids can play a role in dampening excessive excitement in the brain by binding to these CB1 receptors on excited neurons and inhibiting their ability to release any more excitatory neurotransmitters. Naturally, it was thought that these compounds could play an important role in controlling the severity of epileptic seizures. Unfortunately, endocannabinoids tend to have a very short half-life in the body, which has made them near-impossible to study in any great depth.

“There have been lots of studies providing evidence for a connection between seizures and endocannabinoids,” explained senior author Dr Ivan Soltesz, professor of neurosurgery at Stanford University, in a statement. “What sets our study apart is that we could watch endocannabinoid production and action unfold in, basically, real time.”

This new study made use of a new endocannabinoid-visualization method developed by study co-author Dr Yulong Li. The technique involves the bioengineering of certain neurons in the mice so that they would exhibit a modified version of the CB1 receptor. When an endocannabinoid binds to this modified receptor, a fluorescent glow is emitted that is strong enough to be detected by photosensitive instruments.

Using this tool, the researchers behind this new study were able to monitor and localize sub-second chances in fluorescence and correlate that to the endocannabinoid levels present in the mice’s hippocampi as their bodies attempted to suppress the seizure.

2-AG, a double-edged sword

By blocking certain enzymes in the mice that are critical to the production and breakdown of two important endocannabinoids in the brain, 2-AG and anandamide (AEA), the scientists proved that 2-AG is the sole dominant endocannabinoid that surges and breaks down with neuronal activity in the mice, helping to suppress seizures when they happen.

“This previously undetected activity-dependent surge in levels of 2-AG downregulates excitatory neurons’ excessive rhythmic firing during a seizure,” Soltesz said.

The 2-AG levels detected spiked dramatically during induced seizures as the mice’s bodies tried to dampen the severity of the seizure, resulting in a 349 times greater signal increase compared to when the mice would run in place. But the researchers also observed that these levels fell almost immediately, as the 2-AG was hydrolyzed by the enzyme MAGL and converted into arachidonic acid (AA).

This is unfortunate, as AA can be oxygenated by the enzyme COX-2 to produce a type of inflammatory prostaglandin that constricts nearby blood vessels, in turn cutting off the blood oxygen supply to the affected region of the brain. Since most adult seizures begin in the hippocampus, this large release of 2-AG fuels the production of prostaglandins in the temporal lobe, resulting in oxygen deprivation that can cause disorientation and memory problems shortly after the seizure has passed, Soltesz explained.

What does this mean for epilepsy research and 2-AG?

This newly detected 2-AG surge offers a new perspective on neural activity during and after seizures, one that ties seizures to brain oxygen deprivation and stroke-like cognitive defects. It also hints to a new avenue for drug design to tackle epilepsy and temporal lobe seizures.

“A drug that blocks 2-AG’s conversion to arachidonic acid would kill two birds with one stone,” Soltesz explained. “It would increase 2-AG’s concentration, diminishing seizure severity, and decrease arachidonic acid levels, cutting off the production of blood-vessel-constricting prostaglandins.”

With this new sensing technique allowing for the near-real time detection of endocannabinoid levels in specific brain structures, scientists are now better equipped than ever to analyze the intricate goings-on of the endocannabinoid system and evaluate its effects on the body.

Interestingly, while this new research demonstrated that excessive 2-AG levels post-seizure put certain parts of the brain at risk, others have suggested that this endocannabinoid might also be a key factor in protecting the brain against secondary damage following a traumatic brain injury (TBI).

Last December, a research group at the Medical College of Georgia was awarded a $1.4 million grant from the National Institute of Neurological Disorders and Stroke to fund its investigations into how the body’s endocannabinoid system might limit the dangers of secondary inflammation after TBI.

In addition to targeting CB1 receptors in the brain, 2-AG can also target the CB2 receptors present on immune cells and help to module immune function and coordinate the body’s natural anti-inflammatory response. Following a TBI, the plasma membrane surrounding the injured brain cells can rupture, releasing the MAGL enzyme throughout the body. Vaibhav and his colleagues believe that this freed MAGL goes on to break down the 2-AG before it can properly reach the immune cell’s cannabinoid receptors and stimulate the anti-inflammatory response needed for proper healing.

“We are looking into how to suppress MAGL so that you still have enough 2-AG to expedite the recovery process after TBI,” Dr Kumar Vaibhav, a translational neuroscientist and the leader of this research group, told Analytical Cannabis shortly after the funding announcement was made.

To do this, the team is looking to see whether CBD and synthetic versions of 2-AG and AEA might hold promise as a way of inhibiting MAGL in the immune cells, and whether they could be used to tackle the sustained secondary inflammatory response that can endanger TBI patients.


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